Despite considerable research and constantly emerging treatment modalities, the mortality associated with acute respiratory distress syndrome (ARDS) has remained virtually unchanged over the last decade. Clinical studies have been unable to show a reduction in mortality for most therapeutic interventions except for low tidal volume ventilation. Failure to prove a mortality benefit might be a result of the varying severity of ARDS in the patients studied. Nevertheless, positive responses to single supportive measures (inhaled nitric oxide, prone positioning and extracorporeal membrane oxygenation) have been demonstrated in multiple trials. Criteria for administration, weaning and discontinuation of these supportive interventions have never been described in detail. In this context, implementation of an evidence-based algorithm might facilitate clinical management of severe ARDS. This review summarizes the current evidence base and proposes a new treatment algorithm that aims to prioritize the administration of advanced strategies in a multimodal approach for ARDS.